Abstract/Summary The National Cancer Institute, Provocative Question Initiative considers specific high impact questions in cancer research, including what are the molecular and/or cellular mechanisms that underlie the development of cancer therapy induced severe adverse sequelae? Cognitive decrements including impaired learning and memory are common occurrences for the nearly one-half a million Americans of varying ages undergoing radiation therapy for brain cancers each year. Recently, changes to dendritic morphology have been observed in the hippocampus and medial pre-frontal cortex following low to moderate doses of x-rays and charged particles (protons and heavier ions) that are representative of patient doses at the tumor margins (1 to 10 Gy). The resultant morphological deficits have been shown to be temporally coincident with impaired behavioral performance using a variety of cognitive tests in multiple rodent models. Traditionally biophysics models have played a key role in understanding dose delivery and the minimization of normal tissue effects in radiation therapy; however such models have not been considered for the complex structures that comprise various types of neurons in the brain. Our proposal brings together the modeling skills at the University of Nevada, Las Vegas and the laboratory at the University of California, Irvine to develop a predictive stochastic microdosimetric model of radiation induced changes to dendritic morphology in dentate granule cell layer (GCL) and pyramidal cell (PYC) neurons in the hippocampal and medial pre-frontal cortex of transgenic mice using a highly innovative combined computational-experimental approach. Our primary hypothesis is that ionizing radiation (IR) will alter dendritic morphology in neurons of the hippocampus, medial pre-frontal cortex (mPFC), and likely neurons in other brain areas and that biophysics models based on a stochastic microdosimetry can lead to accurate predictions of these changes for different radiation doses, modalities (radiation type) and delivery paradigms (acute vs fractionated). Furthermore, we hypothesize that age related susceptibility will influence the dose and time-dependent radiation response of the CNS, and that these changes will be responsive (i.e. ameliorated) after dose fractionation. Our mechanistic model will provide a quantitative description of changes to dendritic morphology and spine dynamics as dependent on dose and dose fractionation paradigms using x-rays, protons, and carbon beams, the preferred radiation modalities used for the clinical management of brain cancer. In addition, biophysical models will incorporate age, time and dose-dependent radio-dendritic morphology parameters that will be directly tested experimentally, by subjecting young (1 month) and adult (6 month) mice to carefully selected irradiation paradigms, while studying the resulting morphologic changes over time (30 days or longer).